Inhaled Nitric Oxide in Adults with In-Hospital Cardiac Arrest: A Feasibility Study

Abstract Background Resuscitation using a percutaneous mechanical circulatory support device (iCPR) improves survival after cardiac arrest (CA). We hypothesized that the addition of inhaled nitric oxide (iNO) during iCPR might prove synergistic, leading to improved myocardial performance due to lowering of right ventricular (RV) afterload, left ventricular (LV) preload, and myocardial energetics. This study aimed to characterize the changes in LV and RV function and global myocardial work indices (GWI) following iCPR, both with and without iNO, using 2-D transesophageal echocardiography (TEE) and GWI evaluation as a novel non-invasive measurement. Methods In 10 pigs, iCPR was initiated following electrically-induced CA and 10 min of untreated ventricular fibrillation (VF). Pigs were randomized to either 20 ppm (20 ppm, n = 5) or 0 ppm (0 ppm, n = 5) of iNO in addition to therapeutic hypothermia for 5 h following ROSC. All animals received TEE at five pre-specified time-points and invasive hemodynamic monitoring. Results LV end-diastolic volume (LVEDV) increased significantly in both groups following CA. iCPR alone led to significant LV unloading at 5 h post-ROSC with LVEDV values reaching baseline values in both groups (20 ppm: 68.2 ± 2.7 vs. 70.8 ± 6.1 mL, p = 0.486; 0 ppm: 70.8 ± 1.3 vs. 72.3 ± 4.2 mL, p = 0.813, respectively). LV global longitudinal strain (GLS) increased in both groups following CA. LV-GLS recovered significantly better in the 20 ppm group at 5 h post-ROSC (20 ppm: − 18 ± 3% vs. 0 ppm: − 13 ± 2%, p = 0.025). LV-GWI decreased in both groups after CA with no difference between the groups. Within 0 ppm group, LV-GWI decreased significantly at 5 h post-ROSC compared to baseline (1,125 ± 214 vs. 1,835 ± 305 mmHg%, p = 0.011). RV-GWI was higher in the 20 ppm group at 3 h and 5 h post-ROSC (20 ppm: 189 ± 43 vs. 0 ppm: 108 ± 22 mmHg%, p = 0.049 and 20 ppm: 261 ± 54 vs. 0 ppm: 152 ± 42 mmHg%, p = 0.041). The blood flow calculated by the Impella controller following iCPR initiation correlated well with the pulsed-wave Doppler (PWD) derived pulmonary flow (PWD vs. controller: 1.8 ± 0.2 vs. 1.9 ± 0.2L/min, r = 0.85, p = 0.012). Conclusions iCPR after CA provided sufficient unloading and preservation of the LV systolic function by improving LV-GWI recovery. The addition of iNO to iCPR enabled better preservation of the RV-function as determined by better RV-GWI. Additionally, Impella-derived flow provided an accurate measure of total flow during iCPR.

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Cluster randomised comparison of the effectiveness of 100% oxygen versus titrated oxygen in patients with a sustained return of spontaneous circulation following out of hospital cardiac arrest: a feasibility study. PROXY: post ROSC OXYgenation study

BMC Emergency Medicine ◽

10.1186/s12873-018-0214-1 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 10

Author(s):

Matthew Thomas ◽

Sarah Voss ◽

Jonathan Benger ◽

Kim Kirby ◽

Jerry P. Nolan

Keyword(s):

Cardiac Arrest ◽

Feasibility Study ◽

Spontaneous Circulation ◽

Return Of Spontaneous Circulation ◽

Cluster Randomised ◽

Hospital Cardiac Arrest

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Effect of early adjunctive use of oral sildenafil and inhaled nitric oxide on the outcome of pulmonary hypertension in newborn infants. A feasibility study

Journal of Neonatal-Perinatal Medicine ◽

10.3233/npm-16161 ◽

2016 ◽

Vol 9 (3) ◽

pp. 251-259 ◽

Cited By ~ 8

Author(s):

S. Al Omar ◽

H. Salama ◽

M. Al Hail ◽

H. Al Rifai ◽

M. Bunahia ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Feasibility Study ◽

Newborn Infants ◽

Inhaled Nitric Oxide

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Beneficial Effects of Nitric Oxide on Outcomes after Cardiac Arrest and Cardiopulmonary Resuscitation in Hypothermia-treated Mice

Anesthesiology ◽

10.1097/aln.0000000000000149 ◽

2014 ◽

Vol 120 (4) ◽

pp. 880-889 ◽

Cited By ~ 27

Author(s):

Kotaro Kida ◽

Kazuhiro Shirozu ◽

Binglan Yu ◽

Joseph B. Mandeville ◽

Kenneth D. Bloch ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Cardiac Arrest ◽

Cerebral Blood Flow ◽

Brain Injury ◽

Cardiopulmonary Resuscitation ◽

Inhaled Nitric Oxide ◽

Wild Type ◽

Beneficial Effects ◽

Endogenous Nitric Oxide

Abstract Background: Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Although nitric oxide prevents organ injury induced by ischemia and reperfusion, role of nitric oxide during TH after CPR remains unclear. In this article, the authors examined the impact of endogenous nitric oxide synthesis on the beneficial effects of hypothermia after CA/CPR. The authors also examined whether or not inhaled nitric oxide during hypothermia further improves outcomes after CA/CPR in mice treated with TH. Methods: Wild-type mice and mice deficient for nitric oxide synthase 3 (NOS3−/−) were subjected to CA at 37°C and then resuscitated with chest compression. Body temperature was maintained at 37°C (normothermia) or reduced to 33°C (TH) for 24 h after resuscitation. Mice breathed air or air mixed with nitric oxide at 10, 20, 40, 60, or 80 ppm during hypothermia. To evaluate brain injury and cerebral blood flow, magnetic resonance imaging was performed in wild-type mice after CA/CPR. Results: Hypothermia up-regulated the NOS3-dependent signaling in the brain (n = 6 to 7). Deficiency of NOS3 abolished the beneficial effects of hypothermia after CA/CPR (n = 5 to 6). Breathing nitric oxide at 40 ppm improved survival rate in hypothermia-treated NOS3−/− mice (n = 6) after CA/CPR compared with NOS3−/− mice that were treated with hypothermia alone (n = 6; P < 0.05). Breathing nitric oxide at 40 (n = 9) or 60 (n = 9) ppm markedly improved survival rates in TH-treated wild-type mice (n = 51) (both P < 0.05 vs. TH-treated wild-type mice). Inhaled nitric oxide during TH (n = 7) prevented brain injury compared with TH alone (n = 7) without affecting cerebral blood flow after CA/CPR (n = 6). Conclusions: NOS3 is required for the beneficial effects of TH. Inhaled nitric oxide during TH remains beneficial and further improves outcomes after CA/CPR. Nitric oxide breathing exerts protective effects after CA/CPR even when TH is ineffective due to impaired endogenous nitric oxide production.

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Improving Outcomes in Cardiac Arrest With Inhaled Nitric Oxide

Case Medical Research ◽

10.31525/ct1-nct04134078 ◽

2019 ◽

Author(s):

Keyword(s):

Nitric Oxide ◽

Cardiac Arrest ◽

Inhaled Nitric Oxide

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Abstract 12177: Inhaled Nitric Oxide During Cardiopulmonary Resuscitation Improves Functional Outcome and Increases 7-Day-Survival After Prolonged Cardiac Arrest in Rats

Circulation ◽

10.1161/circ.130.suppl_2.12177 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Anne Brücken ◽

Christian Bleilevens ◽

Matthias Derwall ◽

Michael Fries

Keyword(s):

Nitric Oxide ◽

Cardiac Arrest ◽

Cardiopulmonary Resuscitation ◽

Functional Outcome ◽

Statistical Significance ◽

Spontaneous Circulation ◽

Left Ventricular ◽

Inhaled Nitric Oxide ◽

Sprague Dawley ◽

Pulmonary Vasodilator

Introduction: Precordial compressions during cardiac arrest (CA) increase pulmonary vascular resistance (PVR), potentially impeding survival by limiting left ventricular preload. Although used as selective pulmonary vasodilator there is accumulating evidence that inhaled nitric oxide (iNO) also attenuates I/R injury. Hypothesis: Applying iNO during cardiopulmonary resuscitation (CPR) increases resuscitation rates and improves functional outcome after cardiac arrest in rats. Methods: Thirty male Sprague-Dawley rats were subjected to 10 mins of CA and 3 mins of CPR. Animals were randomized to receive either 20 ppm or 40 ppm iNO during CPR until 30 mins after ROSC (return of spontaneous circulation) or no iNO treatment. For all animals a neurological deficit score (NDS) was calculated daily for seven days following the experiment. Results: Inhalation of 20 ppm iNO increased ROSC rates in comparison to animals treated with 40 ppm or without iNO treatment, however this failed to reach statistical significance (control: 7/10; 20ppm iNO: 10/10; 40ppm iNO 6/10). 20 ppm iNO significantly decreased time to ROSC, resulting in a significant reduction of post-arrest lactate levels. Also, significantly higher mean arterial pressures in comparison to control animals were observed. Furthermore, 20 ppm iNO resulted in a significantly higher seven-day-survival in comparison to controls (control: 4/10; 20 ppm iNO: 10/10). All iNO treated animals showed better neurological outcomes, being significant in animals treated with 20 ppm iNO on postoperative day 2- 7. Conclusions: Our study demonstrates that 20 ppm but not 40 ppm iNO during CPR significantly decreases time to ROSC. Furthermore, significantly better seven-day-survival and neurological outcome was noted for 20 ppm iNO in comparison to controls.

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Abstract 10: Transcriptional Profiling of the Neuroprotective Mechanisms of Inhaled Nitric Oxide in a Swine Model of Pediatric Cardiac Arrest

Circulation ◽

10.1161/circ.138.suppl_2.10 ◽

2018 ◽

Vol 138 (Suppl_2) ◽

Author(s):

Marco Hefti ◽

Kumaran Senthil ◽

Constantine D Mavroudis ◽

Michael Karlsson ◽

Johannes Ehinger ◽

...

Keyword(s):

Nitric Oxide ◽

Cardiac Arrest ◽

Synaptic Vesicle ◽

Vesicle Trafficking ◽

Transcriptional Profiling ◽

Inhaled Nitric Oxide ◽

Differentially Expressed ◽

Swine Model ◽

Protective Mechanisms ◽

Illumina Hiseq

Introduction: Neurologic morbidity is common after pediatric cardiac arrest and inhaled nitric oxide (iNO) may be protective. RNA sequencing may have a role in identifying differences in gene expression related to neurologic injury following cardiac arrest and the neuroprotective mechanism of iNO. Hypothesis: We hypothesized that genes related to energetically intensive functions such as synaptic vesicle trafficking would be downregulated after cardiac arrest and that this finding would be less prominent with iNO therapy. Methods: One-month old piglets underwent sham anesthesia or 7 minutes of asphyxia, induction of VF, and randomized and blinded therapy with AHA guideline-based CPR with iNO (iNO + ) or without iNO (iNO - ). Four hours post-ROSC, animals were euthanized and RNA was extracted from cerebral cortical tissue and sequenced on an Illumina HiSeq instrument. STAR was used to align reads to the SusScrofa11.1 reference followed by quantification with sub-reads. Normalization and differential expression analyses were performed using DESeq2 with RIN, RNA concentration, shocks delivered, epinephrine doses, post-ROSC epinephrine use, cerebral blood flow, ETCO 2 , and blood gas values as covariates. Benjamini-Hochberg-adjusted p values <0.05 were considered statistically significant. Results: Sham animals (n=5) and cardiac arrest animals with ROSC (iNO+ n=9; iNO- n=6) were included in analyses. 817 genes were differentially expressed between cardiac arrest and sham. 798 genes were differentially expressed between iNO + and iNO - . 24 genes were differentially expressed in opposite directions in the two comparisons, making them candidates for protective mechanisms of iNO. These included genes related to synaptic vesicle function (RAB27B, PACSIN1, DOC2A) and maintenance of synaptic structure (SH2D5, CA10). Cardiac arrest induced downregulation of synaptic vesicle genes including SNAP25 and synaptophysin, while iNO induced upregulation of others in the same ontology, including synapsins and synaptogamins. Conclusions: Piglets subjected to asphyxial cardiac arrest exhibited downregulation of genes related to synaptic vesicle trafficking. This was partially prevented by treatment with iNO.

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